Rhodium-Catalyzed Regio- and Diastereoselective [3+2] Cycloaddition of gem-Difluorinated Cyclopropanes with Internal Olefins

Direct synthesis of gem-difluorinated carbocyclic molecules represents a longstanding challenge in organic chemistry. Herein, a Rh-catalyzed [3+2] cycloaddition reaction between readily available gem-difluorinated cyclopropanes (gem-DFCPs) and internal olefins has been developed, enabling the efficient synthesis of gem-difluorinated cyclopentanes with good functional group compatibility, excellent regioselectivity and good diastereoselectivity. The resulting gem-difluorinated products can undergo downstream transformations to access various mono-fluorinated cyclopentenes and cyclopentanes. This reaction demonstrates the use of gem-DFCPs as a type of “CF₂” C3 synthon for cycloaddition under transition metal catalysis, which provides potential strategy for synthesizing other gem-difluorinated carbocyclic molecules.     

Regio-selective hydroxylation of gem-difluorinated octanes by alkane hydroxylase (AlkB)

gem-Difluoromethylene substituted molecules constitute a distinct class of fluorinated compounds. In this study, special chemistry has been developed for their preparation based on the highly selective terminal hydroxylation of these gem-difluorinated octanes by AlkB (alkane hydroxylase) from Pseudomonas putida Gpo1 to form gem-difluorinated octan-1-ols. The hydroxylation reaction is performed by whole-cell catalysis. Identification of the distal- and proximal-hydroxylation products was made by ¹H, ¹³C, and ¹⁹F NMR; GC and GC/MSD; and/or by comparison with authentic standards in GC. To the best of our knowledge, we have obtained the first synthesis of 2,2-, 3,3- and 4,4-difluorooctan-1-ols, from simple and inexpensive starting materials.     

Synthesis of optically active gem-difluorocyclopropanes through a chemo-enzymatic reaction strategy

The synthesis of a chiral difluorocyclopropane building block has been accomplished using lipase-catalyzed reaction; the prochiral diacetate of cis-1,3-bishydroxymethyl-2,2-difluorocyclopropane was converted to the corresponding chiral monoacetate by the Alcaligenes lipase (lipase QL)-catalyzed hydrolysis with >99% enantiomeric excess. Enantiomerically pure trans-1,3-bishydroxymethyl-2,2-difluorocyclopropane was also obtained through the Pseudomonas cepacia SL-25 lipase (lipase SL)-catalyzed reaction. The synthesis of the chiral trans,trans-bis-gem-difluorocyclopropane derivatives has been accomplished using the same lipase technology; trans,trans-1,6-bishydroxymethyl-2,2,5,5-tetrafluorobicyclopropane was obtained in optically active form using the lipase SL-catalyzed hydrolysis of the corresponding diacetate.     

Rhodium-Catalyzed Enantioselective 1,4-Oxyamination of Conjugated gem-Difluorodienes via Coupling with Carboxylic Acids and Dioxazolones

The incorporation of fluorine atoms in organics improves their bioactivity and lipophilicity. Catalytic functionalization of gem-difluorodienes represents one of the most straightforward approaches to access fluorinated alkenes. In contrast to the regular 1,3-dienes that undergo diverse asymmetric di/hydrofunctionalizations, the regio- and enantioselective oxyamination of gem-difluorodienes remains untouched. Herein, we report asymmetric 1,4-oxyamination of gem-difluorodiene by chiral rhodium-catalyzed three-component coupling with readily available carboxylic acid and dioxazolone, affording gem-difluorinated 1,4-amino alcohol derivatives. Our asymmetric protocol exhibits high 1,4-regio- and enantioselectivity with utility in the late-stage modification of pharmaceuticals and natural products. Stoichiometric experiments provide evidences for the π-allylrhodium pathway. Related oxyamination was also realized when trifluoroethanol was used as an oxygen nucleophile.     

Iodine(III)-Mediated Migratory gem-Difluorinations: Synthesis of β Transformable Functionality Substituted gem-Difluoroalkanes

Geminal-difluoroalkanes featuring intriguing steric and electronic properties are of great significance in medicinal chemistry, and great progresses have been achieved for their synthesis. In recent years, iodine(III) reagent-mediated migratory gem-difluorination of alkenes has proved to be an efficient and powerful strategy to access to diverse gem-difluoroalkanes, especially those bearing a readily transformable functionality (TF), which are important for rapid assembly of complex gem-difluorinated molecules in a modular and diverse manner. In this review, we systematically summarize the recent development of iodine(III)-mediated migratory gem-difluorination reactions for the synthesis of gem-difluoroalkanes bearing a synthetically versatile TF at the β position. The reaction mechanism and the utilities of the products are also discussed. This review is presented and grouped basically according to the types of transformable functionalities within the products.     

Copper-Catalyzed Enantioselective Hydrosilylation of gem-Difluorocyclopropenes Leading to a Stereochemical Study of the Silylated gem-Difluorocyclopropanes

Optically active cyclopropanes have been widely investigated especially from the views of pharmaceutical and agrochemical industries, and substituting one of the methylenes with the difluoromethylene unit should be promising for developing novel biologically relevant compounds and functional materials. In this paper, the copper-catalyzed enantioselective hydrosilylation of gem-difluorocyclopropenes to provide the corresponding chiral gem-difluorocyclopropanes is presented. The use of copper(I) chloride, chiral ligands including bidentate BINAPs and monodentate phosphoramidites, and silylborane Me₂PhSi-Bpin accompanying sodium tert-butoxide in methanol was appropriate for the enantioselective hydrosilylation of the strained C=C double bond, and the resultant chiral difluorinated three-membered ring was unambiguously characterized. Subsequent activation of the silyl groups in enantio-enriched gem-difluorocyclopropanes showed substantial reduction of the enantiopurity, indicating cleavage of the distal C−C bond leading to the transient acyclic intermediates.     

Effect of gem-Difluorination on the Key Physicochemical Properties Relevant to Medicinal Chemistry: The Case of Functionalized Cycloalkanes

Physico-chemical properties important to drug discovery (pK_a, LogP, and aqueous solubility), as well as metabolic stability, were studied for a series of functionalized gem-difluorinated cycloalkanes and compared to those of non-fluorinated and acyclic counterparts to evaluate the impact of the fluorination. It was found that the influence of the CF₂ moiety on the acidity/basicity of the corresponding carboxylic acids and amines was defined by inductive the effect of the fluorine atoms and was nearly the same for acyclic and cyclic aliphatic compounds. Lipophilicity and aqueous solubility followed more complex trends and were affected by the position of the fluorine atoms, ring size, and even the nature of the functional group present; also, significant differences were found for the acyclic and cyclic series. Also, gem-difluorination either did not affect or slightly improved the metabolic stability of the corresponding model derivatives. The presented results can be used as a guide for rational drug design employing fluorine and establish the first chapter in a catalog of the key in vitro properties of fluorinated cycloalkanes.     

Photoredox-Mediated Reaction of gem-Diborylalkenes: Reactivity Toward Diverse 1,1-Bisborylalkanes

The use of gem-diborylalkenes as radical-reactive groups is explored for the first time. These reactions provide an efficient and general method for the photochemical conversion of gem-diborylalkenes to rapidly access 1,1-bisborylalkanes. This method exploits a novel photoredox decarboxylative radical addition to gem-diborylalkenes to afford α-gem-diboryl carbon-centered radicals, which benefit from additional stability by virtue of an interaction with the empty p-orbitals on borons. The reaction offers a highly modular and regioselective approach to γ-amino gem-diborylalkanes. Furthermore, EPR spectroscopy and DFT calculations have provided insight into the radical mechanism underlying the photochemistry reaction and the stability of the bis-metalated radicals, respectively.     

Reaction of Organometallic Compounds with Polyfluorinated Benzene Derivatives: Synthesis of 1-[3-(2,4-Difluorobenzoyl)-Phenyl]-Propan-1-One

The abnormally high acidity of the aromatic proton placed between two fluorine atoms in the benzene ring renders the compounds with this substitution pattern incompatible with the conventional organometallic compounds in synthetic processes. The synthesis of 1-[3-(2,4-difluorobenzoyl)-phenyl]-propan-1-one via the Stille reaction is reported as a remedy.     

Chemo-, Stereo- and Regioselective Fluoroallylation/Annulation of Hydrazones with gem-Difluorocyclopropanes via Tunable Palladium/NHC Catalysis

Defluorinative manipulation of polyfluorinated molecules has shown great promise due to its granting of synthetic versatility to inert C−F bonds. The development of chemo-, stereo- and regioselective strategies to realize highly efficient formation of either the linear/branched or E/Z products from gem-difluorocyclopropanes (gem-F₂CPs) is a challenging task. Herein, we have realized palladium/NHC-catalyzed fluoroallylation/annulation of hydrazones with gem-F₂CPs that incorporate the hydrazone N₂ moiety into the products. The thermodynamically unstable fluorinated E-allylation products with aryl ketone hydrazones were obtained for the first time, while the di-alkyl ketone hydrazones yielded the monofluorinated products with branched selectivity under similar reaction conditions. With aldehyde hydrazones, two kinds of pyrazoles were obtained via a defluorinative allylation/annulation cascade, in which different carbon atoms of gem-F₂CPs could be incorporated into the pyrazole rings regiospecifically. DFT calculations revealed that the divergent selectivity was kinetically controlled and the final C−C bond formation proceeded through a 7-membered TS.     

Ketyl Radical Anion Mediated Radical Polymerization and Anionic Ring-Opening Polymerization to Give Polymers with Low Molecular Weight Distribution

The development of novel polymerization capable of yielding polymers with low molecular weight distribution (Đ) is essential and significant in polymer chemistry, where monofunctional initiator contains only one initiation site in these polymerizations generally. Here, ketyl radical anion species is introduced to develop a novel Ketyl Mediated Polymerization (KMP), which enables radical polymerization at carbon radical site and anionic ring-opening polymerization at oxygen anion site, respectively. Meanwhile, polymerization and corresponding organic synthesis generally couldn't be performed simultaneously in one pot. Through KMP, organic synthesis and polymerization are achieved in one pot, where small molecules (cyclopentane derivates) and polymers with low Đ are successfully prepared under mild condition simultaneously. At the initiation step, both organic synthesis and polymerization are initiated by single electron transfer reaction with ketyl radical anion formation. Cyclopentane derivates are synthesized through 3–3 coupling reaction and cyclization. Polystyrene and polycaprolactone with low Đ and a full monomer conversion are prepared by KMP via radical polymerization and anionic ring-opening polymerization, respectively. This work therefore enables both organic synthesis and two different polymerizations from same initiation system, which saves time, labour, resource and energy and expands the reaction mode and method libraries of organic chemistry and polymer chemistry.     

Transformations based on ring-opening of gem-difluorocyclopropanes

gem-Difluorocyclopropanes are an important fluorinated class of compounds with applications in medicinal chemistry, material sciences and organic synthesis. The transformations based on their ring-opening reactions have been recognized to be useful methods for rapidly synthesizing various fluorinated organic molecules. In this digest paper, we describe these efforts and highlight their powerfully potential and applications as fluorine-containing synthons in organic chemistry.     

Free Radical Synthetic Protocol for Benzothiazoles via Ring Opening of Benzotriazole: A Two‐step Organic Chemistry Experiment for Undergraduate and Postgraduate Students

The utility and advantages of benzotriazole methodology have been described for the practical synthesis of benzothiazoles. The two‐step synthetic procedure includes nucleophilic acyl substitution followed by benzotriazole ring cleavage under the free radical condition and subsequent cyclization via elimination of molecular nitrogen (N₂). This protocol requires cheap and readily available reagents, and moreover easy to handle, thus can be used to teach undergraduate and postgraduate students about the importance of benzotriazole moiety in organic synthesis, ring cleavage chemistry, cyclization reactions, and use of industrial waste in free radical reactions. Students can also learn some important and common techniques useful in organic chemistry such as monitoring of organic reaction using thin‐layer chromatography and UV, microwave (MW) technique for the synthesis, and column chromatography for the product isolation and structure determination through NMR, MS, and IR spectral analysis of the pure compounds.     

Synthesis of novel gem-difluorinatedcyclopropane hybrids: Applications for DNA cleavage agents switched by photo irradiation

A strong DNA cleavage property switched by photo irradiation was found for 9-anthracenecarboxylic acid substituted gem-difluorocyclopropane derivatives; in particular, a clear contrast in the activity was observed between the enantiomers of (S,S)- and (R,R)-3-aminomethyl-2,2-difluorocyclopropylmethyl 9-anthracenecarboxylate.     

gem-Difluorocyclopropane as core molecule candidate for liquid crystal compounds

The synthesis of a novel chiral gem-difluorocyclopropane building block has been accomplished using chemo-enzymatic reaction protocol; the prochiral diol of 1,4-bis(2,2-difluoro-3-(hydroxymethyl)cyclopropyl)benzene (5) was converted to the corresponding chiral diacetate by Pseudomonas lipase (lipase SL-25, Meito)-catalyzed transesterification with vinyl acetate as acyl donor with >99% enantiomeric excess. Various types of diesters or dialkyl ether were prepared from the diol and their helical twisting power (HTP) was evaluated by addition of 1.0 wt% to a non-chiral nematic liquid crystal host; the HTP was significantly dependent on the structure of ester or ether moieties and diester of diol 5 with isopropylfumalic acid showed the largest HTP.     

A Facile One‐Pot Synthesis of Substituted Quinolines via New Multicomponent Reaction

An efficient synthesis of quinoline derivatives is described via the reaction between ethyl chloropyruvate or alkyl 4‐chloroacetoacetate and activated acetylenic compounds in the presence of nucleophilic form of isatin in water as the solvent. Nucleophilic form of isatin is produced from the reaction of isatin and triethylamin.     

Preparation of gem-difluorocyclopropanes via decomposition of methyl chlorodifluoroacetate by alkali metal halides

The facile decomposition of methyl chlorodifluoroacetate, induced by either lithium chloride/hexamethylphosphoric triamide complex or potassium fluoride/18-Crown-6 complex, has been carried out in the presence of a variety of olefinic substrates to yield the corresponding $\text{gem}$-difluorocyclopropanes. The ester decomposition has been determined to yield “free” difluorocarbene $\text{via}$ a three-step process involving an intermediate chlorodifluoromethide ion.     

Formal Total Synthesis of (+)-Dihydromevinolin via a Chelate-Controlled Intramolecular Diels-Alder Reaction as the Key Step

Compound 3 was synthesized efficiently from enone 4 via (silyloxy)cyclopropanecarboxylate intermediates 6 and 7 . A chelate-controlled intramolecular Diels-Alder reaction of 3 afforded the octahydronaphthalene-2-carboxylate isomer trans- 2b as the main product. This compound was stereoselectively converted into the known dihydromevinolin precursor 1 , thus providing a formal total synthesis of this natural product.     

A new strategy for the synthesis of fluorinated 3,4-dihydropyrimidinones

A new family of 3,4-dihydropyrimidinones (DHPMs) bearing fluorinated substituents at C6 have been prepared from gem-difluorinated nitriles, alkyl 3-butenoates and iso(thio)cyanates. This novel Biginelli-type process relies on the γ-addition of the ester-derived enolate to fluorinated nitriles. A tandem nucleophilic addition aza-Michael reaction sequence completes the synthetic process.     

Selective enhancement effects of silver salts on the transition metal-catalyzed synthesis of gem-difluorinated heterocyclics using 2,2-difluorohomopropargyl amides

The addition of silver salts had an effect on the catalyst activity in the Pd(0)-catalyzed cyclization-coupling tandem reaction, as well as in the Rh(I)-catalyzed Pauson-Khand reaction. The cationic palladium complex generated from Pd(PPh₃)₄ (2.5 mol%) with AgSbF₆ (1.5 equiv.) activates the triple bond of 2,2-difluoropropargylic amides to give the 4,5-disubstituted 3,3-difluoro-γ-lactams, through a sequential 5-endo-dig cyclization and cross-coupling reaction. The γ-lactam was transformed into ring-opened monofluorovinylic compounds after silica-gel chromatography. Pauson-Khand reaction of fluorinated 1,7-enyne amides using catalytic amounts of [Rh(COD)₂]₂ (5 mol%) and AgOTf (20 mol%) gave the corresponding gem-difluorinated bicyclic lactam.